EP1620399B1 - Indolonacetamidderivate, verfahren zu deren herstellung und deren verwendungen - Google Patents

Indolonacetamidderivate, verfahren zu deren herstellung und deren verwendungen Download PDF

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EP1620399B1
EP1620399B1 EP04720863A EP04720863A EP1620399B1 EP 1620399 B1 EP1620399 B1 EP 1620399B1 EP 04720863 A EP04720863 A EP 04720863A EP 04720863 A EP04720863 A EP 04720863A EP 1620399 B1 EP1620399 B1 EP 1620399B1
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indol
dihydro
oxo
chloro
hydrogen
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EP1620399A1 (de
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Jean-Philippe Starck
Benoît KENDA
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UCB Pharma SA
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • the present invention concerns indolone-acetamide derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.
  • European Patent No. 0 162 036 B1 discloses the compound (S)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetamide, which is known under the International Nonproprietary Name of levetiracetam.
  • Levetiracetam a laevorotatory compound, is disclosed as a protective agent for the treatment and prevention of hypoxic and ischemic type aggressions of the central nervous system.
  • This compound is also effective in the treatment of epilepsy, a therapeutic indication for which it has been demonstrated that its dextrorotatory enantiomer (R)- ⁇ -ethyl-2-oxo-1-pyrrolidine acetamide, also known from European Patent No. 0 165 919 B1 , completely lacks activity ( A.J. GOWER et al., Eur. J. Pharmacol., 222, (1992), 193-203 ).
  • Russian patent application SU 841264 discloses 2-(2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide and its anticonvulsant activity.
  • the invention therefore provides a compound having the formula I or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof, wherein
  • the invention provides a compound having the formula I or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof, wherein
  • alkyl is defined as including saturated, monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof and containing 1-20 carbon atoms, preferably 1-6 carbon atoms and more preferably 1-4 carbon atoms for non-cyclic alkyl and 3-8 carbon atoms for cycloalkyl.
  • Alkyl moieties may optionally be substituted by 1 to 5 substituents independently selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, ester or alkylamino.
  • Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, n-butyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl and 3-(dimethylamino)propyl.
  • cycloalkyl refers to a monovalent group of 3 to 18 carbon atoms, preferably 4-8 carbon atoms, derived from a saturated cyclic or polycyclic hydrocarbon which may be substituted by any suitable group including but not limited to one or more moieties selected from groups as described above for the alkyl groups.
  • Preferred cycloalkyl group is cycloheptyl.
  • alkylene represents a divalent alkyl group, having straight or branched moieties, containing 1-12 carbon atoms, preferably 1-6 carbon atoms, and being optionally substituted with any suitable group, including but not limited to one or more moieties selected from groups as described above for the alkyl groups.
  • Preferred alkylene groups are methylene, ethylene, hydroxyethylene, trimethylene or propylene.
  • cycloalkenyl is defined as a cyclic unsaturated hydrocarbon radical having at least one double bond, containing 4-20 carbon atoms, preferably 5-8 carbon atoms, and being optionally substituted with any suitable group, including but not limited to one or more moieties selected from groups as described above for the alkyl groups.
  • Preferred cycloalkenyl group is 6-(hydroxymethyl)cyclohex-3-en-1-yl.
  • aryl is defined as including an organic radical derived from an aromatic hydrocarbon consisting of 1-3 rings and containing 6-30 carbon atoms by removal of one hydrogen, such as phenyl and naphthyl each optionally substituted by 1 to 5 substituents independently selected from halogen, hydroxy, nitro, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylsulfonyl, trifluoromethylthio or pyridinylalkyl.
  • Aryl radicals are preferably phenyl radicals.
  • Preferred aryl groups are phenyl, 3-hydroxyphenyl, 3-fluorophenyl, 3-methylphenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 3-(2-pyridin-2-ylethyl)phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl, 4-methylsulfonylphenyl, 2-nitrophenyl, 2-chloro-6-fluorophenyl, 2-[(trifluoromethyl)thio]phenyl, 2-chlorophenyl or 4-bromophenyl.
  • halogen includes an atom of C1, Br, F, I.
  • nitro represents a group of the formula -NO 2 .
  • hydroxy represents a group of the formula -OH.
  • alkoxy represents a group of formula -OR b wherein R b is an alkyl group, as defined above.
  • esters represents a group of formula -COOR c wherein R c is an alkyl group or an aryl group, as defined above.
  • alkoxycarbonyl represents a group of formula - COOR d wherein R d is an alkyl group, as defined above.
  • amino represents a group of the formula -NH 2 .
  • alkylamino represents a group of formula -NHR e or -NR e R f wherein R e and R f are alkyl group as defined above.
  • alkylsulfonyl as used herein is defined as representing a group of formula -SO 2 -R g , wherein R g is C1-4-alkyl.
  • heterocycle as used herein is defined as including an aromatic or non aromatic cycloalkyl or cycloalkenyl moiety as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure and optionally, one of the carbon of the carbocyclic ring structure may be replaced by a carbonyl.
  • Non-limiting examples of aromatic heterocycles are pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl, pyridinyl, pyrrolyl, thienyl, isothiazolyl, benzimidazolyl, tetrazolyl, isooxazolyl, oxazolyl, thiazolyl, 1,2,4-thiadiazolyl, oxadiazole, pyridazinyl, pyrimidinyl, pyrazinyl, isoindolyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, quinazolinyl, quinolizinyl, naphthyridinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, indolyl, indolizinyl, puriny
  • Non-limiting examples of non aromatic heterocycles are tetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydrobenzazocinyl, dihydroisochromenyl, tetrahydropyranyl, oxooctahydroquinolinyl, dioxolanyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 2-oxo-pyrrolidinyl, 8-thiabicyclo[3.2.1]cyclooctanyl, 1,4-dithiepanyl, tetrahydro-2H-thiopyranyl, azepanyl and azocanyl, optionally substituted by 1 to 5 substituents independently selected from halogen, hydroxy,
  • More preferred non aromatic heterocycles are tetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydro-1-benzazocin-1(2H)-yl, 3,4-dihydro-1H-isochromen-1-yl, tetrahydropyranyl, oxooctahydroquinolinyl and dioxolanyl.
  • heterocycle also includes bicyclic, tricyclic and tetracyclic, spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cycloalkyl ring, a cycloalkenyl ring or another monocyclic heterocyclic ring or where a monocyclic heterocyclic group is bridged by an alkylene group, such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl and 8-azabicyclo(3.2.1)octanyl.
  • pyridinylalkyl represents a group of formula -R h -pyridinyl in which R h is C1-4-alkylene.
  • cyano as used herein, represents a group of the formula -CN.
  • R 2 is hydrogen or C1-4-alkyl.
  • R 2 is hydrogen, methyl or ethyl. More preferably, R 2 is hydrogen or methyl.
  • R 3 is hydrogen; C1-6-alkyl unsubstituted or substituted by 1 to 5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl or alkylamino; C5-7-cycloalkyl; (hydroxymethyl)cyclohexenyl; phenyl unsubstituted or substituted by 1 to 5 substituents selected from halogen, C1-4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl, trifluoromethylthio or pyridinylalkyl; pyridinyl unsubstituted or substituted by methoxy; triazolyl; C1-4-alkoxy; or a group of formula -W-R 8 wherein:
  • R 8 is phenyl unsubstituted or substituted by 1 to 5 substituents selected from halogen, C1-4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl or trifluoromethylthio; furyl unsubstituted or substituted by methyl; pyrazolyl; pyridinyl; morpholinyl; tetrahydrobenzazocinyl; piperidinyl unsubstituted or substituted by methyl; dihydroisochromenyl or dihydroimidazolyl.
  • R 3 is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl, 3-(dimethylamino)propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl, 3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2-ylethyl)phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl, 4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl, 2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl)thio]benzyl, 2-hydroxy-2-phenylethyl, 2-
  • R 3a is hydrogen, C1-4-alkyl or a group of formula wherein m is 1 to 4.
  • R 3a is hydrogen, methyl or tetrahydrofuran-2-ylmethyl. More preferably, R 3a is hydrogen.
  • NR 3 R 3a is piperidinyl unsubstituted or substituted by hydroxy; thiomorpholinyl; thiazolidinyl unsubstituted or substituted by C 1-4-alkoxycarbonyl; 2,5-dihydro-1H-pyrrol-1-yl; 1,4-dioxa-8-azaspiro[4.5]dec-8-yl; 4-oxooctahydro-1(2H)-quinolinyl; or a group of formula wherein R 14 is pyridinyl; phenyl unsubstituted or substituted by halogen, hydroxy, C1-4-alkyl; or a group of formula -V-R 15 wherein V is unsubstituted C1-4-alkylene and R 15 is phenyl or morpholinyl.
  • NR 3 R 3a is 4-pyridin-2-ylpiperazin-1-yl, 4-(3-methylphenyl)piperazin-1-yl, 4-(4-hydroxyphenyl)piperazin-1-yl, 4-(2-phenylethyl)piperazin-1-yl, 4-(2-morpholin-4-ylethyl)piperazin-1-yl, 3-hydroxypiperidta-1-yl, thiomorpholin-4-yl, 4-methoxycarbonyl-1,3-thiazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl or 4-oxooctahydro-1(2H)-quinolinyl.
  • R 5 is halogen or trifluoromethyl.
  • R 6 is hydrogen, C1-6-alkyl or halogen.
  • R 6 is hydrogen, methyl or Cl. More preferably, R 6 is hydrogen.
  • R 7 is hydrogen, methyl or halogen.
  • R 7 is hydrogen, methyl, Br, F or Cl. More preferably, R 7 is hydrogen, Br or F.
  • Combinations of one or more of these preferred compound groups are especially preferred.
  • the invention provides a compound having the formula I or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof, wherein
  • the invention provides a compound having the formula I or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof, wherein
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen
  • R 3a is hydrogen
  • R 5 is halogen or trifluoromethyl
  • R 6 is hydrogen
  • R 7 is hydrogen. Br or F.
  • R 2 when R 2 is C1-20-alkyl, the carbon atom to which R 2 is attached is preferably in the "S"-configuration.
  • Preferred compounds are: 2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (2R)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2-(5-ethyl-2-oxo-2,3-dihydro
  • More preferred compounds are: 2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; (2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2-[2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]acetamide and 2-(5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide.
  • the invention relates to a compound selected from 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide and (2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide.
  • compositions of formula I include therapeutically active, non-toxic base salt forms which the compounds of formula I are able to form.
  • the compounds of formula I containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt forms, e.g. metal or amine salts, by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms include, for example but not limited to, ammonium salts, alkali and earth alkaline metal salts, e.g. lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • salt forms can be converted into the free forms by treatment with an appropriate acid.
  • solvates include for example hydrates, alcoholates and the like.
  • stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem., 45 (1976) 11-30 .
  • the invention also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds of formula I or mixtures thereof (including all possible mixtures of stereoisomers).
  • some compounds having the general formula I may be prepared by desulfurization of a compound of formula II according to the equation:
  • This reaction may be carried out using Raney nickel in an inert solvent, preferably THF, at a temperature comprised between 0 °C and 40 °C, or as described in: Mehta L., Parrick J., Payne F., J. Chem. Research (S) (1998), 190-191.
  • an inert solvent preferably THF
  • Compounds of formula II may be prepared by alkylation of a compound of formula III with a compound of formula IV according to the equation: wherein Hal is a halogen atom, preferably Br or Cl, and R 1 , R 2 , R 3 , R 3a , R 4 , R 5 and R 7 have the same definitions as described above.
  • This reaction may be carried out with a strong base, for example sodium hydride, at a temperature comprised between 0 and 40 °C and in an inert solvent, for example DMF under an inert atmosphere, or as described in patent GB 1,309,692 (UCB).
  • a strong base for example sodium hydride
  • an inert solvent for example DMF under an inert atmosphere
  • This reaction may be carried out at a temperature comprised between 25 and 100 °C in an inert solvent or in acetic acid, in the presence of a Lewis acid, preferably BF 3 .Et 2 O under an inert atmosphere.
  • a Lewis acid preferably BF 3 .Et 2 O under an inert atmosphere.
  • some compounds having the general formula I may be prepared by oxidative bromination of the corresponding indole of formula (VI) followed by the reduction of compound (VII) according to the equation:
  • This reaction may be carried out as described in: Marfat A., Carta M.P., Tetrahedron Lett. (1987), 28, 4027-4031 .
  • Compounds of formula VI may be prepared by alkylation of a compound of formula VIII with a compound of formula IV according to the equation: wherein Hal is an halogen atom, preferably Br or Cl.
  • This reaction may be carried out in the presence of a strong base, preferably sodium hydride, at a temperature comprised between 0 and 40 °C, in an inert solvent, for example DMF, under an inert atmosphere, or as described in patent GB 1,309,692 (UCB).
  • a strong base preferably sodium hydride
  • some compounds having the general formula I may be prepared by halogenation of the corresponding compound of formula I wherein R 5 is a hydrogen with a N-halosuccinimide according to the procedure described in: Castanet A.-S., Colobert F., Broutin P.-E., Tetrahedron Lett. (2002), 43, 5047-5048 .
  • some compounds having the general formula I may be prepared by nitration of the corresponding compound of formula I wherein R 5 is a hydrogen according to procedure described in: Sun L., Rubin J.R., Kraker A.J., Showalter H.D., J. Heterocyclic Chem. (1997), 34, 1399-1405 .
  • some compounds having the general formula I may be prepared by coupling of an amine of formula NHR 3 R 3a with a carboxylic acid derivative of formula IX in the presence of a coupling agent such as dicyclohexylcarbodiimide in dichloromethane or THF.
  • a coupling agent such as dicyclohexylcarbodiimide in dichloromethane or THF.
  • the present invention concerns also the synthesis intermediates of formula II or stereoisomeric forms thereof, wherein
  • the present invention concerns also the synthesis intermediates of formula II or stereoisomeric forms thereof, wherein
  • the synthesis intermediates of formula II are selected from the group consisting of: 2-[2'-oxo-5'-[(triffuoromethyl)oxy]spiro[1,3-dithiolane-2,3'-indol]-1'(2'H)-yl]acetamide; 2-(5'-fluoro-2'-oxospiro[1,3-dithiolane-2,3'-indol]-1'(2'H)-yl)acetamide; 2-[2'-oxo-5'-(trifluoromethyl)spiro[1,3-dithiolane-2,3'-indol]-1'(2'H)-yl]acetamide;
  • the invention concerns also the synthesis intermediates of formula III or stereoisomeric forms thereof, wherein
  • the invention concerns also the synthesis intermediates of formula III or stereoisomeric forms thereof, wherein
  • the synthesis intermediates of formula III are selected from the group consisting of: 5'-[(trifluoromethyl)oxy]spiro[1,3-dithiolane-2,3'-indol]-2'(1'H)-one; 5'-fluorospiro[1,3-dithiolane-2,3'-indol]-2'(1'H)-one; 5'-(trifluoromethyl)spiro[1,3-dithiolane-2,3'-indol]-2'(1'H)-one;
  • the present invention concerns also the synthesis intermediates of formula VI or stereoisomeric forms thereof, wherein
  • the present invention concerns the synthesis intermediates of formula VI or stereoisomeric forms thereof, wherein
  • the synthesis intermediates of formula VI are selected from the group consisting of: 2-(5-chloro-1H-indol-1-yl)propanamide: 2-(5-chloro-1H-indol-1-yl)butanamide; 2-(5-bromo-1H-indol-1-yl)propanamide; 2-(5-bromo-1H-indol-1-yl)acetamide; 2-(5-fluoro-1H-indol-1-yl)acetamide; and 2-(5-chloro-1H-indol-1-yl)acetamide.
  • the present invention concerns also the synthesis intermediates of formula IX or stereoisomeric forms thereof, wherein
  • the present invention concerns the synthesis intermediates of formula IX or stereoisomeric forms thereof, wherein
  • the synthesis intermediate of formula IX is (5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetic acid.
  • the present invention also concerns the synthesis intermediates 2-(7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide and ethyl (5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetate.
  • the compounds according to the invention are useful for the treatment of epilepsy, epileptogenesis, seizure disorders and convulsions.
  • These compounds may also be used for the treatment of Parkinson's disease.
  • These compounds may also be used for the treatment of dyskinesia induced by dopamine replacement therapy, tardive dyskinesia induced by administration of neuroleptic drugs or Huntington Chorea.
  • the compounds according to the invention may also be used for treating other neurological disorders including bipolar disorders, mania, depression, anxiety, attention deficit hyperactivity disorder (ADHD), migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, tremor, essential tremor, simple or complex tics, Tourette syndrome, restless leg syndrome and other movement disorders, neonatal cerebral haemorrhage, amyotrophic lateral sclerosis, spasticity and degenerative diseases, bronchial asthma, asthmatic status and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis.
  • ADHD attention deficit hyperactivity disorder
  • the present invention also concerns a compound having the formula I or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof as defined above for use as a medicament.
  • the present invention concerns also the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of neurological and other disorders such as mentioned above.
  • the present invention concerns the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of epilepsy, Parkinson's disease, dyskinesia, migraine, bipolar disorders, chronic pain, neuropathic pain, or bronchial, asthmatic or allergic conditions.
  • the methods of the invention comprise administration to a mammal (preferably human) suffering from above mentioned conditions or disorders, of a compound according to the invention in an amount sufficient to alleviate or prevent the disorder or condition.
  • the compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 3 to 3000 mg, preferably 25 to 500 mg of active ingredient per unit dosage form.
  • treatment includes curative treatment and prophylactic treatment.
  • curative is meant efficacy in treating a current symptomatic episode of a disorder or condition.
  • prophylactic is meant prevention of the occurrence or recurrence of a disorder or condition.
  • epileptic seizure refers to a chronic neurologic condition characterised by unprovoked, recurrent epileptic seizures.
  • An epileptic seizure is the manisfestation of an abnormal and excessive synchronised discharge of a set of cerebral neurons; its clinical manifestations are sudden and transient.
  • epilepsy as used herein can also refer to a disorder of brain function characterised by the periodic occurrence of seizures. Seizures can be "nonepileptic" when evoked in a normal brain by conditions such as high fever or exposure to toxins or "epileptic” when evoked without evident provocation.
  • seizure refers to a transient alteration of behaviour due to the disordered, synchronous, and rhythmic firing of populations of brain neurones.
  • Parkinsonian symptoms relates to a syndrome characterized by slowness of movement (bradykinesia), rigidity and / or tremor. Parkinsonian symptoms are seen in a variety of conditions, most commonly in idiopathic Parkinsonism (i.e. Parkinson's Disease) but also following treatment of schizophrenia, exposure to toxins/drugs and head injury. It is widely appreciated that the primary pathology underlying Parkinson's disease is degeneration, in the brain, of the dopaminergic projection from the substantia nigra to the striatum. This has led to the widespread use of dopamine-replacing agents (e.g.
  • L-DOPA L-3,4-dihydroxyphenylalanine
  • dopamine agonists as symptomatic treatments for Parkinson's disease and such treatments have been successful in increasing the quality of life of patients suffering from Parkinson's disease.
  • dopamine-replacement treatments do have limitations, especially following long-term treatment. Problems can include a wearing-off of the anti-parkinsonian efficacy of the treatment and the appearance of a range of side-effects which manifest as abnormal involuntary movements, such as dyskinesias.
  • Dyskinesia is defined as the development in a subject of abnormal involuntary movements. This appears in patients with Huntington's disease, in Parkinson's disease patients exposed to chronic dopamine replacement therapy, and in Schizophrenia patients exposed to chronic treatment with neuroleptics. Dyskinesias, as a whole, are characterised by the development in a subject of abnormal involuntary movements. One way in which dyskinesias may arise is as a side effect of dopamine replacement therapy for parkinsonism or other basal ganglia-related movement disorders.
  • migraine means a disorder characterised by recurrent attacks of headache that vary widely in intensity, frequency, and duration.
  • the attacks are commonly unilateral and are usually associated with anorexia, nausea, vomiting, phonophobia, and/or photophobia. In some cases they are preceded by, or associated with, neurological and mood disturbances.
  • Migraine headache may last from 4 hours to about 72 hours.
  • the International Headache Society (IHS, 1988) classifies migraine with aura (classical migraine) and migraine without aura (common migraine) as the major types of migraine.
  • Migraine with aura consists of a headache phase preceded by characteristic visual, sensory, speech, or motor symptoms. In the absence of such symptoms, the headache is called migraine without aura.
  • bipolar disorders refers to those disorders classified as Mood Disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition ( Diagnostic and Statistical Manual of Mental Disorders (DSM-IV TM), American Psychiatry Association, Washington, DC, 1994 ). Bipolar disorders are generally characterised by spontaneously triggered repeated (i.e. at least two) episodes in which the patient's hyperexcitability, activity and mood are significantly disturbed, this disturbance consisting on some occasions of an elevation of mood and increased energy and activity (mania or hypomania), and in other occasions a lowering of mood and decreased energy and activity (depression). Bipolar disorders are separated into four main categories in the DSM-IV (bipolar I disorder, bipolar II disorder, cyclothymia, and bipolar disorders not otherwise specified).
  • manic episode refers to a distinct period during which there is an abnormally and persistently elevated, expansive, or irritable mood with signs of pressured speech and psychomotor agitation.
  • hypomania refers to a less extreme manic episode, with lower grade of severity.
  • major depressive episode refers to a period of at least 2 weeks during which there is either depressed mood or the loss of interest or pleasure in nearly all activities with signs of impaired concentration and psychomotor retardation.
  • mixed episode refers to a period of time (lasting at least 1 week) in which the criteria are met both for a manic episode and for a major depressive episode nearly every day.
  • chronic pain refers to the condition gradually being recognised as a disease process distinct from acute pain. Conventionally defined as pain that persists beyond the normal time of healing, pain can also be considered chronic at the point when the individual realises that the pain is going to be a persistent part of their lives for the foreseeable future. It is likely that a majority of chronic pain syndromes involves a neuropathic component, which is usually harder to treat than acute somatic pain.
  • neurode pain refers to pain due to a dysfunctional nervous system, sometimes occurring following injury to the central nervous system (central pain), but more often caused by damage to peripheral nerves (painful peripheral neuropathy). Neuropathic pain is most likely caused by neural hyperexcitation in partially damaged nerves.
  • neuropathic pain painful reactions appear in response to normally neutral stimuli (allodynia) or as exaggerated reactions to painful stimuli (hyperalgesia). Spontaneous pain, not provoked by external stimuli, also occurs in neuropathic pain, and is the most difficult form of pain to measure and treat.
  • Tics refers to common and often disabling neurological disorders. They are frequently associated with behaviour difficulties, including obsessive-compulsive disorder, attention deficit hyperactivity disorder and impulse control.
  • Tics are involuntary, sudden, rapid, repetitive, nonrhythmic stereotype movements or vocalizations. Tics are manifested in a variety of forms, with different durations and degrees of complexity.
  • Simple motor tics are brief rapid movements that often involve only one muscle group.
  • Complex motor tics are abrupt movements that involve either a cluster of simple movements or a more coordinated sequence of movements.
  • Simple vocal tics include sounds such as grunting, barking, yelping, and thoat clearing.
  • Complex vocal tics include syllables, phrases, repeating other people's words and repeating one's own words.
  • Tremor refers to an involuntary, rhythmical, oscillatory movement of a body part.
  • Tremor can be phenomenologically defined as tremor at rest or associated with an action. Such an action can be postural (maintenance of a limb position), kinetic (movement-related), or intentional (at the end of a purposeful movement).
  • Etiologically, tremor most often occurs in Parkinson's disease (Parkinsonian rest tremor) and in essential tremor (postural and kinetic tremor), which consists of hereditary and age-related forms. Tremor may also occur in dystonia and in multiple sclerosis.
  • Tremor can also be an exaggerated form of normal physiological tremor.
  • tremor frequency is an important criterion to distinguish between various forms of tremor.
  • Essential tremor has the highest incidence of all tremors. As it is age-related, it can be expected to increase in aging populations.
  • tremor may be primarily based on a brainstem (inferior olivary nucleus) - cerebellar dysfunction, whereas Parkinsonian tremor probably originates from abnormal activity within the basal ganglia. Excessive synchronization and/or hyperexcitation in neuronal circuits may underlie tremor activity.
  • the activity of the compounds of formula I, or their pharmaceutically acceptable salts, as anticonvulsants can be determined in the audiogenic seizures model.
  • the objective of this test is to evaluate the anticonvulsant potential of a compound by means of audiogenic seizures induced in sound-susceptible mice, a genetic animal model with reflex seizures.
  • seizures are evoked without electrical or chemical stimulation and the seizure types are, at least in part, similar in their clinical phenomenology to seizures occurring in man ( Löscher W. & Schmidt D., Epilepsy Res. (1998), 2, p. 145-181 ; Buchhalter J.R., Epilepsia (1993), 34, S31-S41 ).
  • Results obtained with compounds of formula I are indicative of a strong pharmacological effect.
  • LBS levetiracetam binding site
  • Activity in any of the above-mentioned indications can of course be determined by carrying out suitable clinical trials in a manner known to a person skilled in the relevant art for the particular indication and/or in the design of clinical trials in general.
  • compounds of formula I or their pharmaceutically acceptable salts may be employed at an effective daily dosage and administered in the form of a pharmaceutical composition.
  • another embodiment of the present invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.
  • one or more of the compounds of formula I or a pharmaceutically acceptable salt thereof is intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to the skilled practitioner.
  • Suitable diluents and carriers may take a wide variety of forms depending on the desired route of administration, e.g., oral, rectal, parenteral or intranasal.
  • compositions comprising compounds according to the invention can, for example, be administered orally or parenterally, i.e., intravenously, intramuscularly or subcutaneously, intrathecally, by inhalation or intranasally.
  • compositions suitable for oral administration can be solids or liquids and can, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing-gums and the like.
  • the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose.
  • these pharmaceutical compositions can also contain a binder such as microcrystalline cellulose, gum tragacanth or gelatine, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or colouring agents or a flavouring agent such as peppermint or methyl salicylate.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatine
  • a disintegrant such as alginic acid
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetener such as sucrose or saccharin
  • colouring agents or a flavouring agent such as peppermint or methyl salicylate.
  • compositions which can release the active substance in a controlled manner are in conventional form such as aqueous or oily solutions or suspensions generally contained in ampoules, disposable syringes, glass or plastics vials or infusion containers.
  • these solutions or suspensions can optionally also contain a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamine-tetra-acetic acid, buffers such as acetates, citrates or phosphates and agents for adjusting the osmolarity, such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamine-tetra-acetic acid, buffers such as acetates, citrate
  • the amount of active ingredient in the pharmaceutical compositions can fall within a wide range of concentrations and depends on a variety of factors such as the patient's sex, age, weight and medical condition, as well as on the method of administration.
  • the quantity of compound of formula I in compositions for oral administration is at least 0.5 % by weight and can be up to 80 % by weight with respect to the total weight of the composition.
  • the compounds of formula I or the pharmaceutically acceptable salts thereof can be administered alone or in combination with other pharmaceutically active ingredients.
  • additional compounds which can be cited for use in combination with the compounds according to the invention are antivirals, antispastics (e.g. baclofen), antiemetics, antimanic mood stabilizing agents, analgesics (e.g. aspirin, ibuprofen, paracetamol), narcotic analgesics, topical anesthetics, opioid analgesics, lithium salts, antidepressants (e.g. mianserin, fluoxetine, trazodone), tricyclic antidepressants (e.g.
  • anticonvulsants e.g. valproic acid, carbamazepine, phenytoin
  • antipsychotics e.g. risperidone, haloperidol
  • neuroleptics e.g. benzodiazepines (e.g. diazepam, clonazepam), phenothiazines (e.g. chlorpromazine), calcium channel blockers, amphetamine, clonidine, lidocaine, mexiletine, capsaicin, caffeine, quetiapine, serotonin antagonists, ⁇ -blocker, antiarrhythmics, triptans, ergot derivatives and amantadine.
  • anticonvulsants e.g. valproic acid, carbamazepine, phenytoin
  • antipsychotics e.g. risperidone, haloperidol
  • neuroleptics e.g. benzodiazepines (e.g. di
  • Examples of compounds inducing neural inhibition mediated by GABA A receptors include the following: benzodiazepines, barbiturates, steroids, and anticonvulsants such as valproate, viagabatrine, tiagabine or pharmaceutical acceptable salts thereof.
  • Benzodiazepines include the 1,4-benzodiazepines, such as diazepam and clonazepam, and the 1,5-benzodiazepines, such as clobazam.
  • Preferred compound is clonazepam.
  • Barbiturates include phenobarbital and pentobarbital.
  • Preferred compound is phenobarbital.
  • Steroids include adrenocorticotropic hormones such as tetracosactide acetate, etc.
  • Anticonvulsants include hydantoins (phenytoin, ethotoin, etc), oxazolidines (trimethadione, etc.), succinimides (ethosuximide, etc.), phenacemides (phenacemide, acetylpheneturide, etc.), sulfonamides (sulthiame, acetoazolamide, etc.), aminobutyric acids (e.g. gamma-amino-beta-hydroxybutyric acid, etc.), sodium valproate and derivatives, carbamazepine and so on.
  • hydantoins phenytoin, ethotoin, etc
  • oxazolidines trimethadione, etc.
  • succinimides ethosuximide, etc.
  • phenacemides phenacemide, acetylpheneturide, etc.
  • sulfonamides sulthiame, ace
  • Preferred compounds include valproic acid, valpromide, valproate pivoxil, sodium valproate, semi-sodium valproate, divalproex, clonazepam, phenobarbital, vigabatrine, tiagabine and amantadine.
  • Examples of compounds modulating neurotransmission mediated by glutamate receptors include the following: NBQX and MK-801 or pharmaceutical acceptable salts thereof.
  • the daily dosage is in the range 3 to 3000 milligrams (mg) of compounds of formula I.
  • the quantity of compound of formula I present is at least 0.5 % by weight and can be up to 33 % by weight with respect to the total weight of the composition.
  • the dosage unit is in the range 3 mg to 3000 mg of compounds of formula I.
  • the daily dose can fall within a wide range of dosage units of compound of formula I and is generally in the range 3 to 3000 mg. However, it should be understood that the specific doses can be adapted to particular cases depending on the individual requirements, at the physician's discretion.
  • the LBS binding compounds provided by this invention and labelled derivatives thereof may be useful as standards and reagents in determining the ability of tested compounds (e.g., a potential pharmaceutical) to bind to the LBS receptor.
  • Labelled derivatives of LBS ligands provided by this invention may also be useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
  • PET positron emission tomography
  • SPECT single photon emission computerized tomography
  • NMR spectra are recorded on a BRUKER AC 250 Fourier Transform NMR Spectrometer fitted with an Aspect 3000 computer and a 5mm 1 H/ 13 C dual probehead or BRUKER DRX 400 FT NMR fitted with a SG Indigo 2 computer and a 5 mm inverse geometry 1 H/ 13 C/ 15 N triple probehead.
  • the compound is studied in DMSO-d 6 .(or CDCl 3 ) solution at a probe temperature of 313 K or 300 K and at a concentration of 20 mg/ml.
  • the instrument is locked on the deuterium signal of DMSO-d 6 (or CDCl 3 ). Chemical shifts are given in ppm downfield from TMS taken as internal standard.
  • HPLC analyses are performed using one of the following systems:
  • the gradient runs from 100 % solvent A (acetonitrile, water, TFA (10/90/0.1, v/v/v)) to 100 % solvent B (acetonitrile, water, TFA (90/10/0.1, v/v/v)) in 7 min with a hold at 100 % B of 4 min.
  • the flow rate is set at 2.5 ml/min and a split of 1/25 is used just before API source.
  • API spectra (+ or -) are performed using a FINNIGAN (San Jose, CA, USA) LCQ ion trap mass spectrometer.
  • APCI source operates at 450 °C and the capillary heater at 160 °C.
  • ESI source operates at 3.5 kV and the capillary heater at 210 °C.
  • Mass spectrometric measurements in DIP/EI mode are performed as follows: samples are vaporized by heating the probe from 50 °C to 250 °C in 5 min. EI (Electron Impact) spectra are recorded using a FINNIGAN (San Jose, CA, USA) TSQ 700 tandem quadrupole mass spectrometer. The source temperature is set at 150 °C.
  • Mass spectrometric measurements on a TSQ 700 tandem quadrupole mass spectrometer (Finnigan MAT, San Jose, CA, USA) in GC/MS mode are performed with a gas chromatograph model 3400 (Varian, Walnut Creek, CA, USA) fitted with a split/splitless injector and a DB-5MS fused-silica column (15 m x 0.25 mm I.D., 1 ⁇ m) from J&W Scientific (Folsom, CA, USA). Helium (purity 99.999 %) is used as carrier gas.
  • the injector (CTC A200S autosampler) and the transfer line operate at 290 and 250 °C, respectively.
  • Sample (1 ⁇ l) is injected in splitless mode and the oven temperature is programmed as follows: 50 °C for 5 min., increasing to 280 °C (23°C/min) and holding for 10 min.
  • the TSQ 700 spectrometer operates in electron impact (EI) or chemical ionization (CI/CH 4 ) mode (mass range 33 - 800, scan time 1.00 sec).
  • the source temperature is set at 150 °C.
  • Preparative chromatographic separations are performed on silicagel 60 Merck, particle size 15-40 ⁇ m, reference 1.15111.9025, using Novasep axial compression columns (80 mm i.d.), flow rates between 70 and 150 ml/min. Amount of silicagel and solvent mixtures as described in individual procedures.
  • Preparative Chiral Chromatographic separations are performed on a DAICEL Chiralpak AD 20 ⁇ m, 100*500 mm column using an in-house build instrument with various mixtures of lower alcohols and C5 to C8 linear, branched or cyclic alkanes at ⁇ 350 ml/min. Solvent mixtures as described in individual procedures.
  • 2-(2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 1 is synthesized according to the method described by Valenta et al. ( Valenta, V.; Holubeck, J.; Svatek, E.; Valchar, M.; Krejci, I.; Protiva, M.; Collect. Czech. Chem. Commun. (1990), 55, 2756-2764 ).
  • Oxindole 1 (1 g, 5.25 mmol) was dissolved in CH 3 CN (20 ml). After addition of the NIS (1.3 g, 5.78 mmol), the TFA (217 ⁇ l, 1.57 mmol) was added and the reaction was allowed at room temperature for 16 h. After evaporation of the solvent, the mixture was triturated in a 10 % aqueous solution of Na 2 S 2 O 3 . The beige solid formed was filtered, washed with water and with ether.
  • Oxindole 1 (1.77 g, 9.3 mmol) was dissolved in 90 % H 2 SO 4 (6 ml) at room temperature, and NCS (1.24 g, 9.3 mmol) was slowly added with stirring. After 2 hours, the mixture was poured into cold water. The precipitate was collected, washed several times with water and then with Et 2 O. After cristallization from EtOH, 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 3 was obtained as a white solid. Yield: 479 mg (23 %). MS (LC-MS, MH + ): 225/227. MP: 226 °C.
  • the Raney Nickel was prepared as an aqueous slurry after removing four fifth of water of the commercial solution.
  • Aqueous Raney nickel (10 ml) was added to a solution of compound 15 (4.06 g, 13.8 mmol) in 40 ml of distilled THF and the mixture was further vigourously stirred at room temperature. When no starting material was detected by thin layer chromatography, the mixture was diluted with THF and filtered through a Celite pad.
  • Zinc dust (23.71 g, 0.58 mol) was added to a stirred solution of compound 31 (theorical: 58.4 mmol) in AcOH (110 ml) at 0°C. After 1 hour, the reaction mixture was filtered through a Celite pad. The filtrate was diluted with AcOEt and cold water. The pH was adjusted to 7 and the layers were separated. The aqueous phase was extracted again with AcOEt. Organic layers were dried over Na 2 SO 4 and concentrated. The beige solid was cristallized in AcOEt and afforded 2-(5-chloro-2-oxo-2,3-dihydro-1 H -indol-1-yl)propanamide 32 as a white solid. Yield: 2.5 g (18 %). MS (LC-MS, MH + ): 239/241.
  • ester 58 was obtained from 5-chloroindole and ethyl bromoacetate (instead of bromo-acetamide) using the methodology described in example 6. MS (GC-MS, M + ⁇ ): 253/255.
  • the synthesis intermediate 2-(7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide may also be prepared according to one of the previous methods.
  • Table 4 Compounds of formula I. No Configuration IUPAC NAME MS (LC-MS, MH + ) ⁇ D (MeOH, 25 °C, 1 %) 2 achiral 2-(5-iodo-2-oxo-2,3-diydro-1H-indol-1-yl)acetamide 316 (GC-MS, M + ⁇ ) 3 achiral 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 225/227 4 achiral 2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 347/349/351 *5 achiral 2-(5-nitro-2-
  • Example 8 LBS Binding Assay.
  • the inhibition constant (K i ) of a compound is determined in competitive binding experiments by measuring the binding of a single concentration of a radioactive ligand at equilibrium with various concentrations of the unlabeled test substance.
  • the concentration of the test substance inhibiting 50 % of the specific binding of the radioligand is called the IC 50 .
  • the equilibrium dissociation constant K i is proportional to the IC 50 and is calculated using the equation of Cheng and Prusoff ( ChengY. et al., Biochem. Pharmacol. (1972), 22, 3099-3108 ).
  • the concentration range usually encompasses 6 log units with variable steps (0.3 to 0.5 log). Assays are performed in mono- or duplicate, each K i determination is performed on two different samples of test substance.
  • Cerebral cortex from 200-250 g male Sprague-Dawley rats are homogenised using a Potter S homogeniser (10 strokes at 1,000 rpm; Braun, Germany) in 20 mmol/l Tris-HCl (pH 7.4), 250 mmol/l sucrose (buffer A); all operations are performed at 4 °C.
  • the homogenate is centrifuged at 30,000xg for 15 min.
  • the crude membrane pellet obtained is resuspended in 50 mmol/l Tris-HCl (pH 7.4), (buffer B) and incubated 15 min at 37 °C, centrifuged at 30,000xg for 15 min and washed twice with the same buffer.
  • the final pellet is resuspended in buffer A at a protein concentration ranging from 15 to 25 mg/ml and stored in liquid nitrogen.
  • Membranes (150-200 ⁇ g of protein / assay) are incubated at 4 °C for 120 min in 0.5 ml of a 50 mmol/l Tris-HCl buffer (pH 7.4) containing 2 mmol/l MgCl 2 , 10 -9 to 2.10 -9 mol/l of [ 3 H]-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide and increasing concentrations of the test substance.
  • the non specific binding (NSB) is defined as the residual binding observed in the presence of a concentration of reference substance (e.g. 10 -3 mol/l levetiracetam) that binds essentially all the receptors.
  • Membrane-bound and free radioligands are separated by rapid filtration through glass fiber filters (equivalent to Whatman GF/C or GF/B; VEL, Belgium) pre-soaked in 0.1 % polyethyleneimine and 10 -3 mol/l levetiracetam to reduce non specific binding.
  • Samples and filters are rinsed by at least 6 ml of 50 mmol/l Tris-HCl (pH 7.4) buffer. The entire filtration procedure does not exceed 10 seconds per sample.
  • the radioactivity trapped onto the filters is counted by liquid scintillation in a ⁇ -counter (Tri-Carb 1900 or TopCount 9206, Camberra Packard, Belgium, or any other equivalent counter).
  • Data analysis is performed by a computerized non linear curve fitting method using a set of equations describing several binding models assuming populations of independent non-interacting receptors, which obey to the law of mass.
  • Example 9 Animal model of sound-susceptible mice.
  • the aim of this test is to evaluate the anticonvulsant potency of a compound in sound-susceptible mice, a genetic animal model with reflex seizures.
  • seizures are evoked without electrical or chemical stimulation and the seizure types are, at least in part, similar in their clinical phenomenology to seizures occurring in man ( Löscher W. & Schmidt D., Epilepsy Res. (1998), 2, 145-181 ; Buchhalter J.R., Epilepsia (1993), 34, S31-S41 ).
  • the experimental design consists of several groups, one group receiving the vehicle control and the other groups different doses of the test-compound.
  • the compounds are administered intraperitoneally 60 minutes before the induction of audiogenic seizures.
  • the range of the doses administered has a logarithmic progression, generally between 1.0 x 10 -5 mol/kg and 1.0 x 10 -3 mol/kg, but lower or higher doses are tested if necessary.
  • mice For testing, the animals are placed in small cages, one mouse per cage, in a sound-attenuated chamber. After a period of orientation of 30 seconds, the acoustic stimulus (90 dB, 10-20 kHz) is delivered for 30 seconds via loudspeakers positioned above each cage. During this interval, the mice are observed and the presence of the 3 phases of the seizure activity namely wild running, clonic and tonic convulsions, is recorded. The proportion of mice protected against wild running, clonic and tonic convulsions, respectively, is calculated.
  • the acoustic stimulus 90 dB, 10-20 kHz
  • an ED 50 value i.e. the dose producing 50 % protection relative to the control group, together with 95 % confidence limits, was calculated using a Probit Analysis (SAS/STAT® Software, version 6.09, PROBIT procedure) of the proportions of protected mice for each of the 3 phases of the seizure activity.

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Claims (19)

  1. Verbindung mit der Formel I oder ein pharmazeutisch akzeptables Salz davon oder stereoisomere Formen davon,
    Figure imgb0057
     wobei
    R1 Wasserstoff ist,
    R2 Wasserstoff oder C1-20-Alkyl ist,
    R3 Wasserstoff, C1-20-Alkyl, C4-8-Cycloalkyl, C5-8-Cycloalkenyl, Aryl, ein aromatischer oder nicht aromatischer Heterocyclus, C1-20-Alkoxy oder eine Gruppe der Formel -W-R8 ist; R3a Wasserstoff, C1-20-Alkyl oder eine Gruppe der Formel:
    Figure imgb0058
     ist;
    oder NR3R3a eine Gruppe der Formel
    Figure imgb0059
     ist;
    R4 Wasserstoff ist;
    R5 Halogen und Trifluormethyl ist;
    R6 Wasserstoff, C1-20-Alkyl oder Halogen ist;
    R7 Wasserstoff, C1-20-Alkyl oder Halogen ist,
    W C1-12-Alkylen, -NH- oder -NHC(=O)- ist,
    X O, S oder NH ist,
    Y O, S, -CR12R13-, NR14- oder -C(=O)- ist,
    R8 Aryl oder ein Heterocyclus ist,
    R9, R10, R10a und R11 unabhängig voneinander aus Wasserstoff, C1-4-Alkyl, Halogen, Hydroxy oder Methoxycarbonyl ausgewählt sind,
    oder R10 und R10s zusammen ein C3-6-Alkylen bilden,
    R12 Wasserstoff, C1-4-Alkyl, Halogen oder Hydroxy ist,
    R13 Wasserstoff ist,
    oder CR12R13 Dioxolanyl ist,
    R14 Aryl, ein Heterocyclus oder eine Gruppe der Formel -V-R15 ist,
    V C1-12-Alkylen ist,
    R15 Aryl oder ein Heterocyclus ist,
    m 1 bis 4 ist,
    n 0 oder 1 ist.
  2. Verbindung mit der Formel I oder ein pharmazeutisch akzeptables Salz davon oder stereoisomere Formen davon,
    Figure imgb0060
     wobei
    R1 Wasserstoff ist,
    R2 Wasserstoff oder C1-4-Alkyl ist,
    R3 Wasserstoff; C1-6-Alkyl, unsubstituiert oder substituiert durch 1 bis 5 Substituenten, ausgewählt aus Halogen, Hydroxy, Alkoxy, Alkoxycarbonyl oder Alkylamino; C5-7-Cycloalkyl; (Hydroxymethyl)cyclohexenyl; Phenyl, unsubstituiert oder substituiert durch 1 bis 5 Substituenten, ausgewählt aus Halogen, C1-4-Alkyl, Hydroxy, Methoxy, Nitro, Methylsulfonyl, Trifluormethylthio oder Pyridinylalkyl; Pyridinyl, unsubstituiert oder substituiert durch Methoxy; Triazolyl; C1-4-Alkoxy oder eine Gruppe der Formel -W-R8 ist,
    R3a Wasserstoff, C1-4-Alkyl oder eine Gruppe der Formel
    Figure imgb0061
     ist,
    oder NR3R3a Piperidinyl, unsubstituiert oder substituiert durch Hydroxy; Thiomorpholinyl; Thiazolidinyl, unsubstituiert oder substituiert durch C1-4-Alkoxycarbonyl; 2,5-Dihydro-1H-pyrrol-1-yl; 1,4-Dioxa-8-azaspiro[4.5]dec-8-yl; 4-Oxooctahydro-1(2H)-chinolinyl oder eine Gruppe der Formel
    Figure imgb0062
     ist,
    Wasserstoff ist,
    R5 Wasserstoff oder Trifluormethyl ist,
    R6 Wasserstoff, C1-6-Alkyl oder Halogen ist,
    R7 Wasserstoff, Methyl oder Halogen ist,
    W C1-4-Alkylen, unsubstituiert oder substituiert durch Halogen, Hydroxy, C1-4-Alkyl oder Alkoxy; -NH- oder -NHC(=O)- ist,
    R8 Phenyl, unsubstituiert oder substituiert durch 1 bis 5 Substituenten, ausgewählt aus Halogen, C1-4-Alkyl, Hydroxy, Methoxy, Nitro, Methylsulfonyl oder Trifluormethylthio; Furyl, unsubstituiert oder substituiert durch Methyl; Pyrazolyl; Pyridinyl; Morpholinyl; Tetrahydrobenzazocinyl; Piperidinyl, unsubstituiert oder substituiert durch Methyl; Dihydroisochromenyl oder Dihydroimidazolyl ist,
    R14 Pyridinyl; Phenyl, unsubstituiert oder substituiert durch Halogen, Hydroxy, C1-4-Alkyl; oder eine Gruppe der Formel -V-R15 ist,
    V unsubstituiertes C1-4-Alkylen ist,
    R15 Phenyl oder Morpholinyl ist,
    m 1 bis 4 ist.
  3. Verbindung mit der Formel I oder ein pharmazeutisch akzeptables Salz davon oder stereoisomere Formen davon,
    Figure imgb0063
     wobei
    R1 Wasserstoff ist,
    R2 Wasserstoff, Methyl oder Ethyl ist,
    R3 Wasserstoff, n-Butyl, Cycloheptyl, 2-Fluorethyl, 3-Hydroxypropyl, 3-Hydroxy-2,2-dimethylpropyl, 1-(Hydroxymethyl)propyl, 3,3,3-Trifluor-2-hydroxypropyl, 3-Ethoxypropyl, 2-Ethoxy-2-oxoethyl, 3-(Dimethylamino)propyl, 6-(Hydroxymethyl)cyclohex-3-en-1-yl, 3-Hydroxyphenyl, 3-Fluorphenyl, 3-(2-Pyridin-2-ylethyl)phenyl, 3,4-Dimethylphenyl, 4-tert-Butylphenyl, Benzyl, 4-Hydroxy-3-methoxybenzyl, 4-Methylsulfonylbenzyl, 2-Nitrobenzyl, 2-Chlor-6-fluorbenzyl, 2-[(Trifluormethyl)thio]benzyl, 2-Hydroxy-2-phenylethyl, 2-(3,4-Dimethoxyphenyl)ethyl, 2-(2-Chlorphenyl)ethyl, 2-(4-Methylphenyl)ethyl, (4-Bromphenyl)amino, Pyridin-3-yl, 6-Methoxypyridin-3-yl, 4H-1,2,4-Triazol-3-yl, Pyridin-4-yl-methyl, (5-Methyl-2-furyl)methyl, 3-(1H-Pyrazol-1-yl)propyl, 2-Morpholin-4-ylethyl, 2-((3,4,5,6-Tetrahydro-1-benzazocin-1(2H)-yl)propyl, 2-(2-Methylpiperidin-1-yl)ethyl, 3,4-Dihydro-1H-isochromen-1-ylmethyl, Methoxy, (4-Pyridinylcarbonyl)amino oder 4,5-Dihydro-1H-imidazol-2-ylamino ist,
    R3a Wasserstoff, Methyl oder Tetrahydrofuran-2-ylmethyl ist,
    oder NR3R3a 4-Pyridin-2-ylpiperazin-1-yl, 4-(3-Methylphenyl)piperazin-1-yl, 4-(4-Hydroxyphenyl)piperazin-1-yl, 4-(2-Phenylethyl)piperazin-1-yl, 4-(2-Morpholin-4-ylethyl)piperazin-1-yl, 3-Hydroypiperdin-1-yl, Thiomorpholin-4-yl, 4-Methoxycarbonyl-1,3-thiazolidin-3-yl, 2,5-Dihydro-1H-pyrrol-1-yl, 1,4-Dioxa-8-azaspiro[4.5]dec-8-yl oder 4-Oxooctahydro-1(2H)-chinolinyl ist,
    R4 Wasserstoff ist,
    R5 Wasserstoff oder Trifluormethyl ist,
    R6 Wasserstoff, Methyl oder Cl ist,
    R7 Wasserstoff, Methyl, Br, F oder Cl ist.
  4. Verbindung nach einem der Ansprüche 1 bis 3, wobei R2 Wasserstoff oder Methyl ist.
  5. Verbindung nach einem der vorstehenden Ansprüche, wobei R3 Wasserstoff ist.
  6. Verbindung nach einem der vorstehenden Ansprüche, wobei R3a Wasserstoff ist.
  7. Verbindung nach einem der vorstehenden Ansprüche, wobei R6 Wasserstoff ist.
  8. Verbindung nach einem der vorstehenden Ansprüche, wobei R7 Wasserstoff, Br oder F ist.
  9. Verbindung nach einem der vorstehenden Ansprüche, wobei R2 C1-20-Alkyl ist und das Kohlenstoffatom, an das R2 gebunden ist, in der "S"-Konfiguration vorliegt.
  10. Verbindung, ausgewählt aus 2-(5-Iod-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamid; 2-(5,7-Dibrom-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamid; (2R)-2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamid; (2S)-2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamid; 2-(5-Ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamid; 2-(5-Fluor-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamid; 2-(5-Brom-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamid; 2-[2-Oxo-5-(trifluormethyl)-2,3-dihydro-1H-indol-1-yl]acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamid; (+)-2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamid; (-)-2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamid; 2-(5-Brom-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamid; (-)-2-(5-Brom-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamid; (+)-2-(5-Brom-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamid; 2-(5-Chlor-7-fluor-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxyphenyl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-fluorphenyl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(2-pyridin-2-ylethyl)phenyl]acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[6-(hydroxymethyl)cyclohex-3-en-1-yl]acetamid; 5-Chlor-1-[2-oxo-2-(4-pyridin-2-yl-piperazin-1-yl)ethyl]-1,3-dihydro-2H-indol-2-on; 5-Chlor-1-{2-[4-(3-methylphenyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-on; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(4-hydroxy-3-methoxybenzyl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)-N-(tetrahydrofuran-2-ylmethyl)acetamid; 5-Chlor-1-[2-(3-hydroxypiperidin-1-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-on; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N'-isonicotinoylacetohydrazid; 5-Chlor-1-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3-dihydro-2H-indol-2-on; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(4H-1,2,4-triazol-3-yl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[4-(methylsulfonyl)benzyl]acetamid; 1-[(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]octahydrochinolin-4(1H)-on; N'-(4-Bromphenyl)-2-(5-chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)acetohydrazid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(6-methoxypyridin-3-yl)acetamid; N-Butyl-2-(5-chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxypropyl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(dimethylamino)propyl]acetamid; 5-Chlor-1-{2-oxo-2-[4-(2-phenylethyl)piperazin-1-yl]ethyl}-1,3-dihydro-2H-indol-2-on; Ethyl-{[(5-chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-acetyl]amino}acetat; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-ethoxypropyl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-fluorethyl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methoxy-N-methylacetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,4-dimethylphenyl)acetamid; N-(4-tert-Butylphenyl)-2-(5-chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[1-(hydroxymethyl)propyl]acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,3,3-trifluor-2-hydroxypropyl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-hydroxy-2-phenylethyl)acetamid; 5-Chlor-1-{2-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-on; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[(5-methyl-2-furyl)methyl]acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(1H-pyrazol-1-yl)propyl]acetamid; Methyl-3-[(5-chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]-1,3-thiazolidin-4-carboxylat; 5-Chlor-1-[2-(2,5-dihydro-1H-pyrrol-1-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-on; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N'-(4,5-dihydro-1H-imidazol-2-yl)acetohydrazid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(2-chlorphenylethyl]acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(4-methylphenyl)ethyl]-acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-morpholin-4-ylethyl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(3,4,5,6-tetrahydro-1-benzazocin-1(2H)-yl)propyl]acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(2-methylpiperidin-1-yl)ethyl]acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-nitrobenzyl)acetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,4-dihydro-1H-isochromen-1-yl-methyl)acetamid; N-(2-Chlor-6-fluorbenzyl)-2-(5-chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-acetamid; N-Benzyl-2-(5-chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methylacetamid; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-{2-[(trifluormethyl)thio]benzyl} acetamid; 5-Chlor-1-[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-on; 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-cycloheptylacetamid; 5-Chlor-1-{2-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-on und 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-pyridin-3-ylacetamid.
  11. Verbindung, ausgewählt aus 2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamid und (2S)-2-(5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamid.
  12. Verbindung mit der Formel II oder stereoisomere Formen davon,
    Figure imgb0064
     wobei
    R1 Wasserstoff ist,
    R2 Wasserstoff oder C1-20-Alkyl ist,
    R3 Wasserstoff, C1-20-Alkyl, C4-8-Cycloalkyl, C5-8-Cycloalkenyl, Aryl, ein aromatischer oder nicht aromatischer Heterocyclus, C1-20-Alkoxy oder eine Gruppe der Formel -W-R8 ist,
    R3a Wasserstoff, C1-20-Alkyl oder eine Gruppe der Formel:
    Figure imgb0065
     ist,
    oder NR3R3a eine Gruppe der Formel
    Figure imgb0066
     ist,
    R4 Wasserstoff ist,
    R5 Wasserstoff oder Trifluormethyl ist,
    R6 Wasserstoff, C1-20-Alkyl oder Halogen ist,
    R7 Wasserstoff, C1-20-Alkyl oder Halogen ist,
    W C1-12-Alkylen, -NH- oder -NHC(=O)- ist,
    X O, S oder NH ist,
    Y O, S, -CR12R13-, -NR14- oder -C(=O)- ist,
    R8 Aryl oder ein Heterocyclus ist,
    R9, R10, R10a und R11 unabhängig voneinander aus Wasserstoff, C1-4-Alkyl, Halogen, Hydroxy oder Methoxycarbonyl ausgewählt sind,
    oder R10 und R10a zusammen ein C3-6-Alkylen bilden,
    R12 Wasserstoff, C1-4-Alkyl, Halogen oder Hydroxy ist,
    R13 Wasserstoff ist,
    oder CR12R13 Dioxolanyl ist,
    R14 Aryl, ein Heterocyclus oder eine Gruppe der Formel -V-R15 ist,
    V C1-12-Alkylen ist,
    R15 Aryl oder ein Heterocyclus ist,
    m 1 bis 4 ist,
    n 0 oder 1 ist.
  13. Verbindung mit der Formel III oder stereoisomere Formen davon,
    Figure imgb0067
     wobei
    R4 Wasserstoff ist,
    R5 Wasserstoff oder Trifluormethyl ist,
    R6 Wasserstoff, C1-20-Alkyl oder Halogen ist,
    R7 Wasserstoff, C1-20-Alkyl oder Halogen ist und mindestens einer von R5, R6 oder R7 nicht Wasserstoff ist.
  14. Verbindung mit der Formel VI oder stereoisomere Formen davon,
    Figure imgb0068
     wobei
    R1 Wasserstoff ist,
    R2 Wasserstoff oder C1-20-Alkyl ist,
    R3 Wasserstoff, C1-20-Alkyl, C4-8-Cycloalkyl, C5-8-Cycloalkenyl, Aryl, ein aromatischer oder nicht aromatischer Heterocyclus, C1-20-Alkoxy oder eine Gruppe der Formel -W-R8 ist, R3a Wasserstoff, C1-20-Alkyl oder eine Gruppe der Formel :
    Figure imgb0069
     ist,
    oder NR3R3a eine Gruppe der Formel:
    Figure imgb0070
     ist,
    R4 Wasserstoff ist,
    R5 Halogen oder Trifluormethyl ist,
    R6 Wasserstoff, C1-20-Alkyl oder Halogen ist,
    R7 Wasserstoff, C2-20-Alkyl oder Halogen ist,
    W C1-12-Alkylen, -NH- oder -NHC(=O)- ist,
    X O, S oder NH ist,
    Y O, S, -CR12R13-, -NR14- oder -C(=O)- ist,
    R8 Aryl oder ein Heterocyclus ist,
    R9, R10, R10a und R11 unabhängig voneinander aus Wasserstoff, C1-4-Alkyl, Halogen, Hydroxy oder Methoxycarbonyl ausgewählt sind,
    oder R10 und R10a zusammen ein C3-6-Alkylen bilden,
    R12 Wasserstoff, C1-4-Alkyl, Halogen oder Hydroxy ist,
    R13 Wasserstoff ist,
    oder CR12R13 Dioxolanyl ist,
    R14 Aryl, ein Heterocyclus oder eine Gruppe der Formel -V-R15 ist, V C1-12-Alkylen ist,
    R15 Aryl oder ein Heterocyclus ist,
    m 1 bis 4 ist,
    n 0 oder 1 ist.
  15. Verbindung mit der Formel IX oder stereoisomere Formen davon,
    Figure imgb0071
     wobei
    R1 Wasserstoff ist,
    R2 Wasserstoff oder C1-20-Alkyl ist,
    R4 Wasserstoff ist,
    R5 Halogen oder Trifluormethyl ist,
    R6 Wasserstoff oder C1-20-Alkyl ist,
    R7 Wasserstoff, C1-20-Alkyl oder Halogen ist.
  16. Verbindung, die aus der Gruppe ausgewählt ist, bestehend aus:
    2-[2'-Oxo-5'-[(trifluormethyl)oxy]spiro[1,3-dithiolan-2,3'-indol]-1'(2'H)-yl]acetamid;
    2-(5'-Fluor-2'-oxospiro[1,3-dithiolan-2,3'-indol]-1'(2'H)-yl)acetamid;
    2-[2'-Oxo-5'-(trifluormethyl)spiro[1,3-dithiolan-2,3'-indol]-1'(2'H)-yl]acetamid;
    5'-[(Trifluormethyl)oxy]spiro[1,3-dithiolan-2,3'-indol]-2'(1'H)-on;
    5'-Fluorspiro[1,3-dithiolan-2,3'-indol]-2'(1'H)-on;
    5'-(Trifluormethyl)spiro[1,3-dithiolan-2,3'-indol]-2'(1,H)-on;
    2-(5-Chlor-1H-indol-1-yl)propanamid;
    2-(5-Chlor-1H-indol-1-yl)butanamid;
    2-(5-Brom-1H-indol-1-yl)propanamid;
    2-(5-Brom-1H-indol-1-yl)acetamid;
    2-(5-Fluor-1H-indol-1-yl)acetamid;
    2-(5-Chlor-1H-indol-1-yl)acetamid;
    (5-Chlor-2-oxo-2,3-dihydro-1H-indol-1-yl)essigsäure.
  17. Pharmazeutische Zusammensetzung, umfassend eine wirksame Menge einer Verbindung nach einem der Ansprüche 1 bis 11 in Kombination mit einem pharmazeutisch akzeptablen Verdünnungsmittel oder Träger.
  18. Verbindung nach einem der Ansprüche 1 bis 11 oder eine pharmazeutische Zusammensetzung nach Anspruch 17 zur Verwendung als Medikament.
  19. Verwendung einer Verbindung nach einem der Ansprüche 1 bis 11 oder einer pharmazeutischen Zusammensetzung nach Anspruch 17 zur Herstellung eines Medikaments für die Behandlung von Epilepsie, Epileptogenese, Krampfleiden, Konvulsionen, Parkinson-Krankheit, Dyskinesie, induziert durch Dopaminsubstitutionstherapie, Spätdyskinesie, induziert durch Verabreichung von Neuroleptika, Huntington Chorea und anderen neurologischen Störungen, einschließlich bipolaren Störungen, Manie, Depression, Angst, Aufmerksamkeits- und Hyperaktivitätsstörung (ADHD), Migräne, Trigeminus- und andere Neuralgie, chronischen Schmerz, neuropathischen Schmerz, Hirnischämie, Herzarrhythmie, Myotonie, Kokainabhängigkeit, Schlaganfall, Myoklonus, Tremor, essenzieller Tremor, einfache oder komplexe Ticks, Tourette-Syndrom, Restless-Legs-Syndrom und andere Bewegungsstörungen, neonatale zerebrale Hämorrhagie, amyotrophe Lateralsklerose, Spastizität und degenerative Krankheiten, Bronchialasthma, asthmatischen Status und allergische Bronchitis, Asthmasyndrom, Bronchialhyperreaktivität und bronchospastische Syndrome sowie Rhinitis allergica und Rhinitis vasomotorica und Rhinokonjunktivitis.
EP04720863A 2003-03-31 2004-03-16 Indolonacetamidderivate, verfahren zu deren herstellung und deren verwendungen Expired - Lifetime EP1620399B1 (de)

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US7964593B2 (en) 2011-06-21
AR043959A1 (es) 2005-08-17
CN100364973C (zh) 2008-01-30
ES2353461T3 (es) 2011-03-02
NO20055026D0 (no) 2005-10-28
ZA200507231B (en) 2006-11-29
KR20050119186A (ko) 2005-12-20
US20100069375A1 (en) 2010-03-18
MXPA05009089A (es) 2005-11-17
HK1089768A1 (en) 2006-12-08
ATE482193T1 (de) 2010-10-15
JP2006522041A (ja) 2006-09-28
CN1768036A (zh) 2006-05-03
US7645887B2 (en) 2010-01-12
EP1620399A1 (de) 2006-02-01
CA2520568A1 (en) 2004-10-14
BRPI0408863A (pt) 2006-04-11
US20070043038A1 (en) 2007-02-22
DE602004029245D1 (de) 2010-11-04
NO20055026L (no) 2005-12-22
WO2004087658A1 (en) 2004-10-14
AU2004226288A1 (en) 2004-10-14
TW200508197A (en) 2005-03-01
RU2005131317A (ru) 2006-02-27

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